The ability of influenza virus to evade immune surveillance through rapid genetic drift and reassortment means that it remains a continuous public health threat. During annual epidemics five to fifteen percent of the worldwide population are typically infected, resulting in three million to five million cases of severe illness and between 250,000 to 500,000 deaths per year (Lambert et al., The New England Journal of Medicine 363:2036-2044; WHO, Influenza (Seasonal) Fact Sheet No. 211). Influenza B virus, like H1 and H3 subtypes of influenza A virus, has caused epidemics in humans (WHO, Influence (Seasonal) Fact Sheet No. 211). In contrast to influenza A, influenza B virus is found almost exclusively in humans and has a much slower mutational rate than that observed for influenza A virus (Carrat et al., Vaccine 25:6852-6862; Nobusawa et al., Journal of Virology 80:3675-3678; Webster et al, The Journal of General Virology 54:243-251). However, co-circulation of two phylogenetically and antigenically distinct lineages, represented by the B/Yamagata/16/88 and B/Victoria/2/87, has caused antigenic variation through genetic reassortment and antigenic drift from cumulative mutations, leading to annual endemics (Hay et al., Philosophical Transactions of the Royal Society of London 356:1861-1870; Lin et al., Virus Research 103:47-52).
The development of vaccines producing broadly reactive antibodies and therapeutic strategies using human monoclonal antibodies (HuMAbs) with global reactivity has recently been gathering great interest. Neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) have been widely used for the treatment of influenza viral infection. However, they have limited efficacy when administered more than 48 hours after the onset of illness (Aoki et al., The Journal of Antimicrobial Chemotherapy 51: 123-129), and widespread use has resulted in the emergence of resistant viral strains (Kiso et al, Lancet 364:759-765; Lowen et al., Infectious Disorders Drug Targets 7:318-328; Reece, Journal of Medical Virology 79:1577-1586). Therefore, new therapeutic strategies that provide potent and broadly cross-protective host immunity are a global public health priority. Thus, the development of novel antibody-based therapies is of great interest (Marasco et al., Nature Biotechnology 25:1421-1434).
Several human monoclonal antibodies (HuMAbs) with broad neutralizing activities were identified against the hemagglutinin (HA) protein in influenza A viruses, including C6261 and F10, which react with group 1 viruses (Ekiert et al., Science 324:246-251; Sui et al., Nature Structural & Molecular Biology 16:265-273), and CR8020, which neutralizes group 2 viruses (Ekiert et al., Science 333:843-850). Another HuMAb, FI6v3, which neutralized both group 1 and group 2 influenza A viruses, was isolated in 2011 (Corti et al., Science 333: 850-856). Although influenza B virus has a much slower mutational rate than that observed for influenza A virus like H1 and H3 subtypes, it has annually caused epidemics in humans (NPL1: Hay et al., Philosophical Transactions of the Royal Society of London 256:1861-1870; NPL2: Lin et al., Virus Research 103:47-52). For influenza B virus, however, broadly neutralizing HuMAbs, CR8033, CR8071 and CR9114, have firstly reported on September 2012 (NPL3: Dreyfus et al., Science 337: 1343-1348). Accordingly, a need exists for broadly neutralizing HuMAb against the influenza B virus.